Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors☆

Grunewald, Gary L.; Seim, Mitchell R.; Regier, Rachel C.; Criscione, Kevin R.

doi:10.1016/j.bmc.2006.11.010

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…Such pseudo-halides, however, cannot be used as precursors for the generation of free radicals or organometallic reagents . Traditional methods for the synthesis of aryl halides (bromides or chlorides) from phenols require either forcing conditions or multi-step procedures . Herein, we report the first example of palladium-catalyzed direct conversion of readily available aryl sulfonate esters to aryl bromides and chlorides.…”

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confidence: 99%

Palladium-Catalyzed Conversion of Aryl and Vinyl Triflates to Bromides and Chlorides

2010

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The palladium-catalyzed conversion of aryl and vinyl triflates to aryl and vinyl halides (bromides and chlorides) has been developed using dialkylbiaryl phosphine ligands. A variety of aryl, heteroaryl and vinyl halides can be prepared via this method in good to excellent yields.Aryl halides are ubiquitous synthetic intermediates in organic chemistry that are used for numerous transformations. 1 They are also present in a wide variety of natural products, pharmaceuticals and agrochemicals. 2 Therefore, the development of general and regioselective methods for the preparation of functionalized aryl halides is of great importance. Sulfonate esters, often referred to as pseudo-halides, can be employed as alternatives to aryl halides in many cross-coupling reactions. 3 Such pseudo-halides, however, cannot be used as precursors for the generation of free radicals 4 or organometallic reagents. 1 Traditional methods for the synthesis of aryl halides (bromides or chlorides) from phenols require either forcing conditions 5 or multi-step procedures. 6 Herein, we report the first example of palladium-catalyzed direct conversion of readily available aryl sulfonate esters to aryl bromides and chlorides.Although a catalytic method has not yet been reported, several mechanistically related metal-mediated carbon-halogen bond-forming processes have been published. 7 For example, the reductive elimination of aryl halides from Pt(IV), 8 Ni(III), 9 Pd(IV), 10 and Pd(III) 11 has been demonstrated. In addition, the reductive elimination of aryl halides from arylpalladium(II) halide complexes in the presence of a large excess of P(t-Bu) 3 has been reported. 12,13 A number of copper 14 -and nickel 15 -mediated halide exchange reactions have also been developed in which carbon-halogen reductive elimination processes are proposed to take place.Despite these advances in aryl-halide bond formation, to the best of our knowledge, there are few examples of the catalytic conversion of an aryl sulfonate to an aryl halide 16 including the ruthenium-catalyzed conversion of 2-naphthyl triflate to 2-bromonaphthalene 16b and our recent report of the palladium-catalyzed conversion of aryl triflates to aryl fluorides. 17 This prompted us to query whether we could uncover a catalytic process to convert aryl triflates into corresponding aryl bromides and chlorides; and results are disclosed herein.Catalysts based on dialkylbiaryl monophosphines 1-4, which have been successfully utilized as ligands in numerous transformations, 17,18 were initially examined for the conversion of sbuchwal@mit.edu.

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Palladium-Catalyzed Conversion of Aryl and Vinyl Triflates to Bromides and Chlorides

2010

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“…Two different hPNMT inhibitors, 1 and 2, have been reported to inhibit the enzyme with K i values of 0.28 μM and 0.063 μM, respectively (radiochemical assay). 52 It has been shown that these two ligands bind to different conformations of the hPNMT binding site (Figure 6A). Both compounds engage in significant hydrophobic interactions, but the larger ligand (2) positions a p-chlorophenyl group in a cavity that is hidden in the hPNMT/1 complex.…”

Section: Journal Of Chemical Theory and Computationmentioning

confidence: 99%

A Collective Variable for the Rapid Exploration of Protein Druggability

Cuchillo¹,

Pinto-Gil²,

Michel³

2015

J. Chem. Theory Comput.

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An efficient molecular simulation methodology has been developed for the evaluation of the druggability (ligandability) of a protein. Previously proposed techniques were designed to assess the druggability of crystallographic structures and cannot be tightly coupled to molecular dynamics (MD) simulations. By contrast, the present approach, JEDI (Just Exploring Druggability at protein Interfaces), features a druggability potential made of a combination of empirical descriptors that can be collected "on-the-fly" during MD simulations. Extensive validation studies indicate that JEDI analyses discriminate druggable and nondruggable protein binding site conformations with accuracy similar to alternative methodologies, and at a fraction of the computational cost. Since the JEDI function is continuous and differentiable, the druggability potential can be used as collective variable to rapidly detect cryptic druggable binding sites in proteins with a variety of MD free energy methods. Protocols for applications to flexible docking problems are outlined.

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“…However, all compounds synthesised were actually less active than the parent H-substituted analogue. The authors suggest that this illustrates that there are limitations to the extent to which predictions based on docking studies can be employed to guide chemistry [66].…”

Section: The Crystallisation Conditions Are Relevant For Drug Designmentioning

confidence: 99%

Limitations and lessons in the use of X-ray structural information in drug design

Davis

St-Gallay

Kleywegt

2008

Drug Discovery Today

140

108

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IntroductionThe drug discovery industry has never been under such pressure to deliver as it is today. While R&D costs spiral higher, attrition statistics in clinical development show no signs of improvement and may actually be getting worse. For example, the FDA highlighted in March 2004 that a drug entering phase 1 clinical development in the year 2000 was less likely to reach the market than one that entered clinical development in 1985 [1]. It is a truism that much of the fate of a drug candidate in clinical development is embedded in the chemical structure and, hence, is in the control of the chemist at the point of design. Clearly, there are serious limitations on what drug designers have so far learnt about the relationship between chemical structure and attrition through clinical development.Drug designers are ever-optimistic, and the hope is that an increasing understanding of the interactions of drug candidates with their protein targets, at the molecular level, may allow quality to be built into drug candidates at the design stage. Indeed, there are a growing number of targets that we are trying to inhibit or activate for which we do understand the relationship between inhibition or activation of the target at the molecular level and their pathophysiological effect. Advances in structural and molecular biology, as well as in biophysics, have led to the determination of high-resolution atomic structures of many of the protein targets of drug discovery projects. For instance, p38 kinase is a target that is well validated in the clinic with respect to its role in inflammation, and many high-resolution crystal structures are available. The same is true for thrombin for anti-thrombosis and renin for hypertension, iNOS for inflammation, EGF receptor tyrosine kinase for cancer, as well as many antibacterial and antiviral targets. Crystal structures of some of the most important drug-metabolising enzymes are also known [2-7], which potentially enables the structure-based rational optimisation of potency, selectivity and metabolism. However, routine control of potency, selectivity and metabolism based on the use of structural information has yet to become a reality.While high-resolution protein structure information can be derived by both NMR spectroscopy and X-ray crystallography, most structures by far have been determined by crystallographic methods. The application of NMR spectroscopy to routine protein structure determination is limited, as it requires large quantities of soluble, multiply labelled protein, considerable time and is limited to comparatively small proteins. Solid-state NMR spectroscopy is being applied to Reviews KEYNOTE REVIEWThe structure model of the designed compound shown with the 2Fo-Fc map contoured at 1s, showing only weak density around the putative position of the ethylamine sidechain.

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Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors☆

Cited by 10 publications

References 31 publications

Palladium-Catalyzed Conversion of Aryl and Vinyl Triflates to Bromides and Chlorides

Palladium-Catalyzed Conversion of Aryl and Vinyl Triflates to Bromides and Chlorides

A Collective Variable for the Rapid Exploration of Protein Druggability

Limitations and lessons in the use of X-ray structural information in drug design

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